Colorectal cancer is the third most prevalent cancer in the United States, with nearly 150,000 new cases diagnosed each year. Despite efforts to improve early detection and treatment, over one-third of patients die annually from this disease. The most deadly aspect of colorectal cancer, metastatic disease, is also the least understood. Our inadequate understanding of the underlying molecular mechanisms involved during metastatic conversion of a primary cancer, and our lack of a comprehensive view of how the cancer cell is transformed, are the primary hurdles for detection, targeting and eradication of metastatic cancer cells. We have recently shown that circulating macrophages spontaneously fuse with cancer cells both in vitro and in vivo systems. Further, we have evidence that the resulting cell fusion hybrids have undergone nuclear reprogramming such that they retain both macrophage and cancer cell transcriptomes. Our observations suggest the intriguing possibility that macrophage-cancer cell fusion represents an under-appreciated process to explain how cancer cells become reprogrammed to express behaviors that are traditionally attributed to blood cells, including migration, altered adhesion, and extravasation; and therefore have the potential to drive metastatic disease. Our long-range research goal is to understand the role of macrophage-cancer cell fusion in mediating metastatic spread of cancer to facilitate development of effective therapeutic targets for metastatic cancer cells by blocking cell fusion. This study is designed to investigate the physiologic contribution of macrophage-cancer fusion to metastatic spread of disease. Based upon our evidence that the cancer cell genome is reprogrammed after fusing with macrophages, we hypothesize that macrophage-tumor cell fusion hybrids functionally acquire macrophage-like behaviors and contribute to the progression of cancer in humans. Guided by insights revealed from our transcriptome profiling, macrophage-cancer cell fusion hybrid behavior and long-term properties will be tested in both in vitro and in vivo systems, harnessing the power of both mouse models and human tissues. These studies provide a novel mechanism for cancer cell reprogramming, and may provide new leads for therapeutic intervention of the most deadly stage of cancer progression.